Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Kulkarni, Tejaswini; O’Reilly, Philip; Antony, Veena B.; Gaggar, Amit; Thannickal, Victor J.

doi:10.1165/rcmb.2015-0166ps

Cited by 109 publications

(87 citation statements)

References 116 publications

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“…2). It is worth noting that these pathways share analogies to those leading to pulmonary fibrosis, wound healing and tumour growth [7–9]. Similarities and differences of adipose ECM remodelling in comparison to cancer ECM dynamics are highlighted in the following section.…”

Section: Proposed Model For How Ecm-receptor Interaction Is Linkedmentioning

confidence: 99%

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Adipose extracellular matrix remodelling in obesity and insulin resistance

Lin

Chun

2016

Biochemical Pharmacology

179

130

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The extracellular matrix (ECM) of adipose tissues undergoes constant remodelling to allow adipocytes and their precursor cells to change cell shape and function in adaptation to nutritional cues. Abnormal accumulation of ECM components and their modifiers in adipose tissues has been recently demonstrated to cause obesity-associated insulin resistance, a hallmark of type 2 diabetes. Integrins and other ECM receptors (e.g. CD44) that are expressed in adipose tissues have been shown to regulate insulin sensitivity. It is well understood that a hypoxic response is observed in adipose tissue expansion during obesity progression and that hypoxic response accelerates fibrosis and inflammation in white adipose tissues. The expansion of adipose tissues should require angiogenesis; however, the excess deposition of ECM limits the angiogenic response of white adipose tissues in obesity. While recent studies have focused on the metabolic consequences and the mechanisms of adipose tissue expansion and remodelling, little attention has been paid to the role played by the interaction between peri-adipocyte ECM and their cognate cell surface receptors. This review will address what is currently known about the roles played by adipose ECM, their modifiers, and ECM receptors in obesity and insulin resistance. Understanding how excess ECM deposition in the adipose tissue deteriorates insulin sensitivity would provide us hints to develop a new therapeutic strategy for the treatment of insulin resistance and type 2 diabetes.

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Section: Proposed Model For How Ecm-receptor Interaction Is Linkedmentioning

confidence: 99%

“…A similar concept has been proposed in the biology of the skeletal muscle and liver, which was recently reviewed elsewhere [6]. Despite a novel perception in the context of obesity and insulin resistance, ECM–ECM receptor pathways have been long implicated in the biology of pulmonary fibrosis, wound healing, and tumour growth [7–9]. …”

Section: Introductionmentioning

confidence: 96%

Adipose extracellular matrix remodelling in obesity and insulin resistance

Lin

Chun

2016

Biochemical Pharmacology

179

130

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“…These mesenchymal cells secrete additional paracrine factors, such as hydrogen peroxide (16,55), angiotensin-II (43, 57), Fas-ligand (12,58), and TGF-␤1 (14,51), that may potentiate or perpetuate injury/apoptosis of AECs. In turn, the accumulation of a highly cross-linked and stiff matrix may perpetuate mesenchymal activation and progressive fibrosis (27,70) (Fig. 3).…”

Section: Epithelial-mesenchymal Cross Talkmentioning

confidence: 99%

Alveolar epithelial disintegrity in pulmonary fibrosis

Kulkarni

Andrade

Zhou

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by progressive decline in lung function, resulting in significant morbidity and mortality. Current concepts of the pathogenesis of IPF primarily center on dysregulated epithelial cell repair and altered epithelial-mesenchymal communication and extracellular matrix deposition following chronic exposure to cigarette smoke or environmental toxins. In recent years, increasing attention has been directed toward the role of the intercellular junctional complex in determining the specific properties of epithelia in pulmonary diseases. Additionally, recent genomewide association studies suggest that specific genetic variants predictive of epithelial cell dysfunction may confer susceptibility to the development of sporadic idiopathic pulmonary fibrosis. A number of genetic disorders linked to pulmonary fibrosis and familial interstitial pneumonias are associated with loss of epithelial integrity. However, the potential links between extrapulmonary clinical syndromes associated with defects in epithelial cells and the development of pulmonary fibrosis are not well understood. Here, we report a case of hereditary mucoepithelial dysplasia that presented with pulmonary fibrosis and emphysema on high-resolution computed tomography. This case illustrates a more generalizable concept of epithelial disintegrity in the development of fibrotic lung diseases, which is explored in greater detail in this review article.

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“…The TGFβ1 signaling pathway is widely regarded as the master regulator of fibrogenesis in vitro and in vivo 29 . In order to investigate whether metformin inhibits the profibrotic effect of TGFβ1 in vitro, primary lung fibroblasts isolated from 10 IPF patients were treated with 2 ng/mL rhTGFβ1 (or vehicle) for 72 h and then treated with 5 mM metformin (or vehicle) for 72 h ( Fig.…”

Section: Metformin Inhibits Tgfβ1-mediated Fibrogenesis In Vitromentioning

confidence: 99%

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

Kheirollahi

Wasnick

Biasin

et al. 2018

Preprint

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Idiopathic pulmonary fibrosis is a fatal, incurable lung disease in which the intricate alveolar network of the human lung is progressively replaced by fibrotic scars, eventually leading to respiratory failure. Myofibroblasts are the effector cells that lead to abnormal deposition of extracellular matrix proteins and therefore mediate fibrotic disease not only in the lung but also in other organs. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug, metformin, exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung myofibroblasts derived from human patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-tolipofibroblast transdifferentiation. Detailed pathway analysis showed that the reduction of collagen synthesis was largely AMPK-dependent, whereas the transdifferentiation of myo-to lipofibroblasts occurred in a BMP2-PPARγ-dependent fashion and was largely AMPK-independent. Our data report an unprecedented role for metformin in lung fibrosis, thus warranting further therapeutic evaluation.

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Matrix Remodeling in Pulmonary Fibrosis and Emphysema

Cited by 109 publications

References 116 publications

Adipose extracellular matrix remodelling in obesity and insulin resistance

Adipose extracellular matrix remodelling in obesity and insulin resistance

Alveolar epithelial disintegrity in pulmonary fibrosis

Metformin induces lipogenic differentiation in myofibroblasts to reverse mouse and human lung fibrosis

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